The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Efficient Strict-Binning Particle-in-Cell Algorithm for Multi-Core SIMD Processors

International audienceParticle-in-Cell (PIC) codes are widely used for plasma simulations. On recent multi-core hardware, performance of these codes is often limited by memory bandwidth. We describe a multi-core PIC algorithm that achieves close-to-minimal number of memory transfers with the main memory, while at the same time exploiting SIMD instructions for numerical computations and exhibiting a high degree of OpenMP-level parallelism. Our algorithm keeps particles sorted by cell at every time step, and represents particles from a same cell using a linked list of fixed-capacity arrays, called chunks. Chunks support either sequential or atomic insertions, the latter being used to handle fast-moving particles. To validate our code, called Pic-Vert, we consider a 3d electrostatic Landau-damping simulation as well as a 2d3v transverse instability of magnetized electron holes. Performance results on a 24-core Intel Sky-lake hardware confirm the effectiveness of our algorithm, in particular its high throughput and its ability to cope with fast moving particles

Structure of an Enzyme-Derived Phosphoprotein Recognition Domain

Membrane Associated Guanylate Kinases (MAGUKs) contain a protein interaction domain (GKdom) derived from the enzyme Guanylate Kinase (GKenz). Here we show that GKdom from the MAGUK Discs large (Dlg) is a phosphoprotein recognition domain, specifically recognizing the phosphorylated form of the mitotic spindle orientation protein Partner of Inscuteable (Pins). We determined the structure of the Dlg-Pins complex to understand the dramatic transition from nucleotide kinase to phosphoprotein recognition domain. The structure reveals that the region of the GKdom that once served as the GMP binding domain (GBD) has been co-opted for protein interaction. Pins makes significantly more contact with the GBD than does GMP, but primarily with residues that are conserved between enzyme and domain revealing the versatility of the GBD as a platform for nucleotide and protein interactions. Mutational analysis reveals that the GBD is also used to bind the GK ligand MAP1a, suggesting that this is a common mode of MAGUK complex assembly. The GKenz undergoes a dramatic closing reaction upon GMP binding but the protein-bound GKdom remains in the ‘open’ conformation indicating that the dramatic conformational change has been lost in the conversion from nucleotide kinase to phosphoprotein recognition domain

Mechanisms for the Evolution of a Derived Function in the Ancestral Glucocorticoid Receptor

Understanding the genetic, structural, and biophysical mechanisms that caused protein functions to evolve is a central goal of molecular evolutionary studies. Ancestral sequence reconstruction (ASR) offers an experimental approach to these questions. Here we use ASR to shed light on the earliest functions and evolution of the glucocorticoid receptor (GR), a steroid-activated transcription factor that plays a key role in the regulation of vertebrate physiology. Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs—reduced sensitivity to all hormones and increased selectivity for glucocorticoids—are derived. Although the mechanisms for the evolution of glucocorticoid specificity have been identified, how reduced sensitivity evolved has not yet been studied. Here we report on the reconstruction of the deepest ancestor in the GR lineage (AncGR1) and demonstrate that GR's reduced sensitivity evolved before the acquisition of restricted hormone specificity, shortly after the GR–MR split. Using site-directed mutagenesis, X-ray crystallography, and computational analyses of protein stability to recapitulate and determine the effects of historical mutations, we show that AncGR1's reduced ligand sensitivity evolved primarily due to three key substitutions. Two large-effect mutations weakened hydrogen bonds and van der Waals interactions within the ancestral protein, reducing its stability. The degenerative effect of these two mutations is extremely strong, but a third permissive substitution, which has no apparent effect on function in the ancestral background and is likely to have occurred first, buffered the effects of the destabilizing mutations. Taken together, our results highlight the potentially creative role of substitutions that partially degrade protein structure and function and reinforce the importance of permissive mutations in protein evolution

Serotype distribution of remaining pneumococcal meningitis in the mature PCV10/13 period: Findings from the PSERENADE Project

Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5-7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites (N = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites (N = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed

Invasive Pneumococcal Disease in Calgary During the Sars-CoV-2 Pandemic 2020

During the Sars-CoV-2 pandemic in 2020, many countries shut down schools and businesses in an effort to slow transmission of the virus. As some businesses reopened, increased public health protocols, mask wearing, hand sanitizer, and personal protective equipment use remained. The shut down and public health restrictions for person-to-person interaction, resulted in a decline of other transmissible diseases as well as Sars-CoV-2. In Calgary, the incidence of invasive disease due to Streptococcus pneumoniae declined to much lower levels than would be expected in early spring and remained low until December 2020. This decline occurred despite no changes in vaccine use and uptake.Othe

Pneumococcal Disease Trends in the Post-Vaccine Era in Calgary, Canada: An Interrupted Time Series Analysis

12th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-12), Toronto, Canada, June 19-23, 2022Background: In 2002 the 4-dose 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in Calgary for vaccination of children, followed by the 3-dose 13-valent vaccine (PCV13) in 2010. Methods: We conducted an interrupted time series analysis on incidence of IPD per quarter allowing for change in trends in 2002 and 2010. We included models for IPD overall and age and serotype restricted models. Results: The incidence of PCV7 IPD (all ages) decreased after PCV7 introduction in 2002 (P<0.001) and was sustained after PCV13 introduction in 2010. In children, the incidence of PCV13 (less PCV7 ST) IPD increased in children after PCV7 introduction (P<0.001) and decreased after PCV13 introduction (P=0.002). After PCV7 introduction, overall IPD incidence was lower in children, but not significant, (P=0.054) and was unchanged in adults (P=0.4721). After PCV13 introduction, overall IPD incidence was unchanged in children (P=0.88) and increased in adults (P<0.001). Conclusions: PCV7 IPD has declined in the post-PCV period, but overall IPD had not declined significantly and was increasing in adults prior to the precipitous decline observed in 2021, during the COVID-19 pandemic. PCV13 serotypes, as well as non-vaccine serotypes, continue to cause disease, including outbreaks of serotype 4, 5, and 8. It is unclear whether the change from 4 doses to 3 doses of PCV has reduced overall vaccine effectiveness

Footnotes to a war

Keith Windschuttle's book The Fabrication of Aboriginal History opened a fresh and ugly chapter in our "culture wars". Here, four writers look at what we've learned from a year of bitter debate